1. Gluconeogenesis is the process by which the body produces glucose from non-carbohydrate substrates during periods of fasting or starvation. It occurs primarily in the liver and kidney. 2. Three irreversible steps in glycolysis present thermodynamic barriers that must be bypassed through new reactions to allow the formation of glucose from substrates like lactate, glycerol, and amino acids. 3. The Cori and glucose-alanine cycles help dispose of excess lactate produced in tissues like muscle and integrate anaerobic glycolysis with gluconeogenesis. The HMP shunt provides an alternative pathway for glucose oxidation and generates NADPH.

1. INTERMEDIARY
METABOLISM OF
CARBOHYDRATES
(DAY:3: GLUCONEOGENESIS &
HMP SHUNT)
Dr. Ifat Ara Begum
Assistant Professor
Dept. of Biochemistry
Dhaka Medical College
Dhaka

3. GLUCONEOGENESIS
The process of converting non-
carbohydrate precursors to
glucose /glycogen
It meets the need of the body for
glucose when sufficient
carbohydrate is not available from
diet/glycogen reserve
As a constant supply of glucose is
essential especially for nervous
system and erythrocyte, failure of
gluconeogenesis is usually fatal

4. CONTD
The major substrates are the
glucogenic amino acids, lactate,
glycerol, pyruvate, propionate,
intermediated of TCA cycle.
Liver (90%) and kidney (10%) are the
major gluconeogenic tissues.

5. CONTD
Nature: Anabolic
ATP requirement: 6 ATP to make 1
molecule of glucose from 2 molecules of
pyruvate or lactate
Source of ATP: Oxidation of FA
Hormonal control: Insulin (-), Glucagon
(+), Cortisol (+)
Importance:
a)Glucose homeostasis in fasting &
starvation
b)Disposal of lactic acid & glycerol in
normal state

6. REACTIONS OF
GLUCONEOGENESIS:
THERMODYNAMIC BARRIERS
In glycolysis, glucose is converted into
pyruvate; in gluconeogenesis, pyruvate
is converted into glucose.
Mostly gluconeogenesis is the reversal
of glycolysis.

7. CONTD
Three nonequilibrium reactions in
glycolysis catalyzed by hexokinase,
phosphofructokinase and pyruvate
kinase are considered as
thermodynamic barriers which prevent
simple reversal of glycolysis for glucose
synthesis.
New steps needed to bypass these 3
irreversible steps of glycolysis

8. CONTD
First bypass : Formation of
Phosphoenolpyruvate from pyruvate
Second bypass : Formation of Fructose-
6-phosphate from fructose 1,6-
bisphosphate
Third bypass : Formation of Glucose by
hydrolysis of glucose 6-phosphate

9. CONTD

10. CONTD
First bypass (Formation of PEP from
pyruvate): Phosphoenolpyruvate is
formed from pyruvate by way of
oxaloacetate through the action of
pyruvate carboxylase
and
phosphoenolpyruvate carboxykinase
 Pyruvate carboxylase is a
mitochondrial enzyme, whereas the
other enzymes of gluconeogenesis are
cytoplasmic.

12. CONTD
Mitochondrial pyruvate carboxylase
catalyzes the carboxylation of pyruvate
to oxaloacetate, an ATP-requiring
reaction in which the vitamin biotin is
the coenzyme.
(Biotin binds CO2 from bicarbonate as
carboxybiotin prior to the addition of
the CO 2 to pyruvate)

13. CONTD
Oxaloacetate, is then reduced to
malate inside the mitochondrion for
transport to the cytosol. The reduction
is accomplished by an NADH-linked
malate dehydrogenase.
When malate has been transported
across the mitochondrial membrane, it
is reoxidized to oxaloacetate by an
NAD+-linked malate dehydrogenase in
the cytosol.

14. CONTD
A second enzyme,
phosphoenolpyruvate carboxy kinase,
catalyzes the decarboxylation and
phosphorylation of oxaloacetate to
phosphoenolpyruvate using GTP as the
phosphate donor.

15. BIOLOGICAL SIGNIFICANCE OF OA
DECARBOXYLATION
In liver and kidney, the reaction of
succinate thiokinase in the citric acid
cycle produces GTP (rather than ATP as
in other tissues)
This GTP is used for the reaction of
phosphoenolpyruvate carboxykinase,
thus providing a link between citric acid
cycle activity and gluconeogenesis to
prevent excessive removal of
oxaloacetate for gluconeogenesis, which
would impair citric acid cycle activity.

16. CONTD
Second bypass (Formation of Fructose 6-
phosphate from fructose 1,6-
bisphosphate) :
Fructose 1,6-bisphosphatase catalyzes
this hydrolysis.
In most tissues, gluconeogenesis ends
here. Free glucose is not generated;
rather, the glucose 6phosphate is
processed in some other fashion,
notably to form glycogen.

17. CONTD
One advantage to ending
gluconeogenesis at glucose 6-
phosphate is that, unlike free
glucose, the molecule cannot diffuse
out of the cell.

18. CONTD
Third bypass (Formation of Glucose
from glucose-6-phosphate) : This final
step does not take place in the
cytosol.
G-6-phosphate is transported into the
lumen of the ER, where it is
hydrolyzed to glucose by glucose 6-
phosphatase, which is bound to the
membrane.
An associated Ca2+binding stabilizing
protein is essential for phosphatase
activity.

19. ANOTHER BYPASS TO FORM
GLYCOGEN
In the kidney, muscle and especially the
liver, G-6-P can be shunted toward
glycogen if blood glucose levels are
adequate.
The reactions necessary for glycogen
synthesis are an alternate bypass series of
reactions
The G-6-P can be converted to G-1-P by
phosphoglucose mutase
G-1-P is then converted to UDP glucose
(the substrate for glycogen synthase) by
UDP-glucose pyro phosphorylase, a
reaction requiring hydrolysis of UTP.

21. A. ENTRY OF GLUCOGENIC AA IN
PATHWAY OF GLUCONEOGENESIS

22. B. ENTRY OF LACTATE IN TO
PATHWAY OF GLUCONEOGENESIS
Lactate is formed in skeletal
muscles, when the rate of
glycolysis exceeds the rate of
oxidative metabolism.
Lactate is readily converted in to
pyruvate by the action of LDH

23. C. ENTRY OF PROPIONATE IN TO
PATHWAY OF GLUCONEOGENESIS
It enters gluconeogenesis via TCA cycle
After esterification with CoA, propionyl
CoA is carboxylated to D-
methylmalonyl-CoA.

24. CONTD
Enzyme needed (serially):
 Propionyl-CoA- carboxylase (biotin
dependent enzyme)
 Methylmalonyl CoA Racemase
 Methylmalonyl CoA mutase (B12
dependent enzyme)

25. D. ENTRY OF GLYCEROL IN TO
PATHWAY OF GLUCONEOGENESIS

26. WHY FATTY ACIDS FAILS TO MAKE
GLUCOSE
once glucose is converted to acetyl CoA
there is no method of getting back to
glucose.
The pyruvate dehydrogenase reaction
that converts pyruvate to acetyl CoA is
not reversible

27. CONTD
Because lipid metabolism produces
acetyl CoA via beta-oxidation, there can
be no conversion to pyruvate or
oxaloacetate that may have been used
for gluconeogenesis
Further, the two carbons in the acetyl
CoA molecule are lost upon entering the
citric acid cycle as 2 CO2 .

28. CONTD
If acetyl CoA could enter into TCA cycle
without help of OAA and at the end of
the cycle, it could come out as OAA,
then it would be possible to make
glucose from acetyl CoA.

29. CORI CYCLE
Even in aerobic condition, lactate is
produced continuously in:
 Cells without mitochondria (RBC)
Cells with few mitochondria (WBC,
retina, renal medulla)
Avascular tissues (lens, cornea)
Amplification of lactate production by
sk. muscle in anaerobic condition/
hypoxia
Disposal of this lactic acid occurs by
CORI cycle

30. CONTD
CORI cycle integrates anaerobic
glycolysis & gluconeogenesis

31. CONTD
 Importance of CORI cycle:
Prevention of lactic acid accumulation
& lactic acidosis

32. GLUCOSE-ALANINE CYCLE

33. CONTD
 Importance of glucose-alanine cycle:
I. Allows muscle glycogen to contribute
glucose to blood during starvation
II.Allows transfer of NH3 (NH2) from
muscle to liver to convert it into urea

36. HMP SHUNT/ PENTOSE PO4
PATHWAY
Alternative pathway for oxidation
of glucose
Not for energy production
Site: liver, adipose tissues, RBC,
macrophage, lactating mammary
gland, adrenal cortex, testes, ovary
(i.e. endocrine glands concerned
with steroid synthesis)

37. CONTD
Compartment: Cytosol
Nature: Catabolic
Rate limiting enzyme: G6PD
Coenzyme needed: NADP
ATP: Neither consumed nor
produced

39. CONTD
Stages: 2 stages
I. Irreversible oxidative
decarboxylation of G-6-P to ribulose-
5-P
II.Reversible nonoxidative conversion
of ribulose-5-P to G-6-P

41. IMPORTANCE OF HMP SHUNT
It is an alternative pathway of glucose
oxidation
Provides NADP2H to:
1. Help :
i. in reductive synthesis of FA, steroid,
cholesterol etc
ii.Detoxifying function of liver to convert
toxic subs in to nontoxic forms
iii.in reduction of H2O2
iv.Synthesis of NO / EDRF

42. CONTD
 2. Prevent hemolysis by facilitating
anti oxidant activity in RBC
 3. Facilitate superoxide & free radical
production in phagocytes through
oxygen dependent myeloperoxidase
system to kill bacteria & other
pathogens
Provides ribose sugar for synthesis of
nucleotides & NA

43. HMP SHUNT VS. GLYCOLYSIS
HMP shunt Glycolysis
Alternative pathway
of glucose oxidation
Major pathway of
glucose oxidation
Produce NADP2H Produce NAD2H
CO2 is produced
directly
Do not produce CO2
Site: selective tissues Site: All tissues
No ATP
produced/consumed.
Ribose & NADP2H are
produced
Meant for ATP
production

44. G6PD DEFICIENCY
Hemolytic anemia
Chronic granulomatosis